THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See USPI.

Transcription

1 PFIZER INC. These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert. For publications based on this study, see associated bibliography. PROPRIETARY DRUG NAME/GENERIC DRUG NAME: Celebrex / THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See USPI. NCT NO.: Not applicable PROTOCOL NO.: N PROTOCOL TITLE: A Randomized, Double-Blind, Multicenter, Active-Controlled Parallel- Group Study to Evaluate the Efficacy and Safety of Suspension Compared to Naproxen Suspension in Patients with JRA Study Center(s): A total of 45 sites enrolled subjects: 1 site each in Belgium, Canada, Denmark, France, Slovakia, Slovenia, and Sweden; 2 sites each in Mexico and the Russian Federation; 3 sites each in Peru and Spain; 4 sites in Brazil; 5 sites in Germany; and 19 sites in the United States. Study Initiation and Completion Dates: 16 October 2002 to 11 April 2005 Phase of Development: Phase 3 Study Objective(s): The primary objective of the study was to evaluate the efficacy, safety, and pharmacokinetics (PK) of celecoxib suspension for the treatment of the signs and symptoms of juvenile rheumatoid arthritis (JRA) as compared to naproxen suspension (a standard active comparator). Secondary objectives of the study were to compare the pharmacokinetic (PK) profile of celecoxib suspension in children with JRA to an adult cohort with rheumatoid arthritis (RA); obtain PK information to guide the dosing of celecoxib in the pediatric population; and evaluate various Definitions of Improvement (DOI) for use in the JRA population METHODS Study Design: This was a 12-week, randomized, double-blind, active-controlled, parallel-group, multicenter, non-inferiority study comparing the efficacy and safety of celecoxib suspension to naproxen suspension in subjects with JRA, with an optional 12-week open-label treatment phase. An adult cohort with RA participated in a 2-week, assigned, open-label study to compare the PK profile of celecoxib suspension in children with JRA. Number of Patients (planned and analyzed): Planned: A total of 75 pediatric subjects per treatment arm for a total of 225 subjects were Page 1

2 planned. Additionally, 40 adults were planned for the open-label treatment phase. Analyzed: A total of 242 subjects were enrolled into the pediatric study and randomized: 77 subjects in the celecoxib 3 mg/kg BID treatment group, 82 subjects in the celecoxib 6 mg/kg BID treatment group, and 83 subjects in the naproxen treatment group. In addition, 43 adults entered the study and 40 completed the open-label phase while 3 patients withdrew from the study. Diagnosis and Main Criteria for Inclusion: Subjects, ages 2 through 16, with a diagnosis of polyarticular or pauciarticular course of JRA (as determined by the American College of Rheumatology [ACR] criteria) or with systemic onset JRA who had polyarticular or pauciarticular course were eligible. Onset of JRA must have occurred prior to the subject s 16 th birthday. Subjects had to have 1 swollen joint and 1 joint with limitation of motion. Joints with limited range of motion could have been the same as the swollen joints. Subjects must have had a physician and parent global assessment at screening of 10 mm on a 100 mm VAS scale. Adult RA subjects were at least 18 years of age and had a diagnosis of RA by ACR criteria. Study Treatment: Subjects with JRA who met all the inclusion and exclusion criteria for the study were randomly assigned to 1 of the 3 treatment groups: 50 mg/5 ml oral suspension (target dose: 3 mg/kg twice daily [BID]), celecoxib 100 mg/5 ml oral suspension (target dose: ), or naproxen oral suspension 125 mg/5 ml (target dose: 7.5 mg/kg BID) in a 1:1:1 ratio. The volume of study medication administered was determined by the subject s weight at the Baseline visit. Subjects who entered the open-label phase received celecoxib 100 mg/5 ml oral suspension (approximately ) for 12 weeks. The volume of open-label study medication administered was determined by the subject s weight at the Week 12 visit. The open-label study medication was to be taken BID (before breakfast and before bedtime). The adult RA cohort took celecoxib 200 mg BID as a 100 mg/5 ml suspension for 2 weeks. Efficacy Evaluations: The primary evaluation was the percent of subjects improved as defined by the JRA-30 DOI (also known as the ACR Pediatric 30 Criterion) at Week 12. The JRA-30 DOI criterion included the following 6 core set variables: Physician s Global Assessment of Disease Activity; Parent s Global Assessment of Overall Well Being (Childhood Health Assessment Questionnaire [CHAQ] subsection); Parent s Assessment of Physical Function (CHAQ Disability Index); number of joints with active arthritis; number of joints with limited range of motion; and laboratory marker of inflammation (C-reactive protein [CRP]). Other evaluations were the Parent s Assessment of Child s Arthritis Pain (visual analogue scale [VAS]) (CHAQ subsection) and the Pediatric Quality of Life Inventory, as well as, various Definitions of Improvement for use in the JRA population. Pharmacokinetic, Pharmacodynamic, and/or Other Evaluations: The PK profile of celecoxib suspension was compared in children with JRA versus the PK profile in the adult cohort who took celecoxib 200 mg BID as 100 mg/5 ml suspension. Each JRA subject was to have 1 blood draw per treatment visit (4 in all). Visit times were staggered so as to obtain a wide distribution of sampling times relative to the time of the most recent dose. The sample time relative to dose at each treatment visit was determined by the JRA subject s randomization Page 2

3 number. Subjects whose randomization number ended in an even number (even numbered) or whose randomization number ended in an odd number (odd numbered) had different sampling times. For the adult RA cohort, blood samples for PK analysis were drawn at the Baseline visit and at Week 2. The Week 2 PK samples were drawn at the following times: predose (trough), 15 and 30 minutes postdose, 1, 2, 4, and 6 hours postdose. Safety Evaluations: All randomized subjects (adult RA subjects and JRA subjects) who received at least 1 dose of study medication were included in the analysis of safety. All adverse events (AEs) were coded (MedDRA Version 2.3) and summarized by treatment group. The incidence of treatment-emergent AEs was tabulated by treatment group and body system. The incidence of treatment-emergent AEs was displayed by severity and attribution. In addition, the incidence of AEs causing withdrawal and serious AEs were tabulated. A developmental history to capture any deleterious treatment effects on growth and development was conducted by the investigators. Any adverse change in development or loss of developmental milestones occurring during the course of the trial was then to have been captured by the investigator as an AE. A slit lamp examination to assess for uveitis was performed by an ophthalmologist. Clinical laboratory data were summarized and treatment groups were compared. Mean changes in vital signs during the study were evaluated. A disseminated intravascular coagulation (DIC) panel (fibrinogen degradation products [FDP], D-dimer, and fibrinogen) was collected on any subject who experienced a flare of systemic features of JRA. Statistical Methods: Efficacy: Improvement according to the JRA-30 DOI criterion is defined as 30% improvement in 3 Core Set variables and at most 1 with a worsening of >30%. Improvement (or worsening) of an efficacy parameter is defined by percentage change from Baseline. Baseline for the doubleblind phase was the last observation prior to the first dose of double-blind study medication. In the statistical analysis plan, the efficacy portion of the primary objective of the study was addressed by the primary analysis of the JRA-30 DOI. The non-inferiority of the celecoxib suspension to the naproxen suspension in treating the signs and symptoms of JRA was evaluated using 95% 2-sided binomial confidence intervals (large sample normal approximation) for the difference in the percent improved subjects, as defined by the JRA-30 criterion, at Weeks 2, 4, 8, and 12 (Final visit), ie, celecoxib 3 mg/kg BID naproxen and celecoxib 6 mg/kg BID naproxen. Non-inferiority of celecoxib was claimed if the lower limit of the 95% 2-sided confidence interval for the difference in the percent responders (celecoxib naproxen) was above -25%. The primary endpoint was the Week 12 time point. Pairwise treatment comparisons using the Chi-Square test were performed for the 3 treatment groups with regard to the proportion of JRA-30 DOI responders, at Weeks 2, 4, 8, and 12 (Final visit). Change from Baseline at each visit was analyzed for Physician s Global Assessment of Disease Activity, Parent s Global Assessment of Overall Well Being (CHAQ subsection), Parent s Page 3

4 Assessment of Physical Function (CHAQ Disability Index), Parent s Assessment of Child s Arthritis Pain (VAS) (CHAQ subsection), number of joints with active arthritis, number of swollen and tender/painful joints assessed separately, number of joints with limited range of motion, CRP, and PedsQL. These analyses were carried out using an ANCOVA model with treatment group as factor and Baseline values as a covariate. The last efficacy assessment was carried forward if a subject withdrew prior to the Final visit at 12 weeks. No adjustments were made for multiple comparisons. Safety: The incidence of AEs by treatment group within body system and causing withdrawal were compared between treatment groups using a Fisher s Exact test. Clinical laboratory data were summarized and treatment groups were compared. An ANCOVA using pair-wise treatment comparisons with treatment group as a factor and Baseline value as a covariate was used to analyze any between-treatment group differences from double-blind Baseline to Final. Scatter diagrams and shift tables were used to depict the shift in laboratory values from the double-blind Baseline to Final visits. The incidence of extreme laboratory values was compared between treatment groups using Fisher s Exact test. Changes in vital signs from Baseline to Weeks 12, 24, and Final visit were compared between treatment groups with an ANCOVA using pair-wise treatment comparisons with treatment group as a factor and Screening value as a covariate. The incidence of extreme vital signs was tabulated by treatment group for the Final visit. The extreme criterion included 15% increase/decrease for BP and pulse. RESULTS Subject Disposition and Demography: A total of 242 subjects with JRA were randomized. All 242 subjects received at least 1 dose of study medication and 212 subjects completed the trial (67 subjects in the celecoxib 3 mg/kg BID treatment group, 71 subjects in the celecoxib 6 mg/kg BID treatment group, and 74 subjects in the naproxen treatment group). Table S1 summarizes the subject disposition. Page 4

5 Table S1 Subject Disposition Double-blind Phase 3 mg/kg BID Naproxen Total Randomized to Double-Blind Phase 77 (100.0%) 82 (100.0%) 83 (100.0%) 242 (100.0%) Completed Double-Blind Phase 67 (87.0%) 71 (86.6%) 74 (89.2%) 212 (87.6%) Early Withdrawal During Double-Blind 10 (13.0%) 11 (13.4%) 9 (10.8%) 30 (12.4%) Phase Reason for Early Withdrawal a Adverse Event 3 (3.9%) 7 (8.5%) 3 (3.6%) 13 (5.4%) Protocol Violation 0 (0.0%) 1 (1.2%) 1 (1.2%) 2 (0.8%) Consent Withdrawn 4 (5.2%) 2 (2.4%) 1 (1.2%) 7 (2.9%) Lost to Follow-Up 1 (1.3%) 0 (0.0%) 0 (0.0%) 1 (0.4%) Lack of Efficacy 2 (2.6%) 1 (1.2%) 4 (4.8%) 7 (2.9%) a Mutually exclusive and exhaustive categories 3 mg/kg BID= 50 mg/5 ml, = 100 mg/5 ml, Naproxen 7.5 mg/kg BID= 125 mg/5 ml. Most of the subjects with JRA were white (58% of subjects) females (71% of subjects), between the ages of 8 to 16 years (72% of subjects). Treatment groups appeared well matched with respect to duration of JRA, onset of systemic features of JRA, and presence of pauciarticular or polyarticular course JRA. Ten subjects who completed the double-blind phase of the study did not enter the open-label phase. Subject disposition regarding reasons for not entering the openlabel phase of the study is summarized in Table S2. Table S2 Subject Disposition Reason for Not Entering Open-label Phase 3 mg/kg BID Naproxen Total Completed Double-Blind/Did Not Enter 5 (6.5%) 1 (1.2%) 4 (4.8%) 10 (4.1%) Open-Label Reason for Not Entering Open-Label a Protocol Violation 1 (1.3%) 0 (0.0%) 0 (0.0%) 1 (0.4%) Consent Withdrawn 3 (3.9%) 1 (1.2%) 3 (3.6%) 7 (2.9%) Lack of Efficacy 0 (0.0%) 0 (0.0%) 1 (1.2%) 1 (0.4%) Sponsor s Decision 1 (1.3%) 0 (0.0%) 0 (0.0%) 1 (0.4%) a Mutually exclusive and exhaustive categories 3 mg/kg BID= 50 mg/5 ml, = 100 mg/5 ml, Naproxen 7.5 mg/kg BID= 125 mg/5 ml. A total of 202 subjects were enrolled into the open-label phase, and all 202 subjects received at least 1 dose of open-label study medication and the majority (96.5%) completed the open-label phase. Subject disposition for those entering the open-label phase is summarized in Table S3. Page 5

6 Table S3 Subject Disposition Open-label Phase Naproxen Total 3 mg/kg BID Enrolled Open-Label/Study Med Taken 62 (100.0%) 70 (100.0%) 70 (100.0%) 202 (100.0%) Completed Open-Label Phase 60 (96.8%) 66 (94.3%) 69 (98.6%) 195 (96.5%) Early Withdrawal During Open-Label Phase 2 (3.2%) 4 (5.7%) 1 (1.4%) 7 (3.5%) Reason For Early Withdrawal a Adverse Event 1 (1.6%) 1 b (1.4%) 1 (1.4%) 3 (1.5%) Protocol Violation 1 (1.6%) 0 (0.0%) 0 (0.0%) 1 (0.5%) Consent Withdrawn 0 (0.0%) 2 (2.9%) 0 (0.0%) 2 (1.0%) Protocol Specific Withdrawal Criteria 0 (0.0%) 1 (1.4%) 0 (0.0%) 1 (0.5%) a Mutually exclusive and exhaustive categories b One subject was listed as withdrawing due to an AE on the AE CRF page and listed as withdrawing due to protocol specific withdrawal criteria on the end of study page. The subject withdrew due to flare of systemic features of JRA. The correct reason for withdrawal was protocol specific withdrawal criteria. 3 mg/kg BID= 50 mg/5 ml, = 100 mg/5 ml, Naproxen 7.5 mg/kg BID= 125 mg/5 ml. Forty-three adult subjects were randomized and 40 completed the study. The mean age of the adult subjects was 52.8 years. All were white and the majority of the adult subjects (63%) were women. Efficacy Results: Primary Efficacy: The percentage of subjects who met the JRA-30 DOI was 69% for celecoxib 3 mg/kg BID, 80% for celecoxib, and 67% for naproxen 7.5 mg/kg (Table S4). Noninferiority of celecoxib was claimed if the lower limit of the 95% 2-sided confidence interval for the difference in the percent improved (celecoxib naproxen) was above -25%. At Week 12 (primary time point), both celecoxib treatment groups demonstrated non-inferiority to naproxen, as well as at all other time points during the double-blind phase (Weeks 2, 4, 8, and 12). Numerical treatment differences favored celecoxib over naproxen at Weeks 4, 8, and 12, and celecoxib 3 mg/kg BID at Weeks 2, 4, 8, and 12. Page 6

7 Table S4 JRA-30 Definition of Improvement (ITT Cohort) at Week 12 3 mg/kg BID N = 77 N = 82 Naproxen N = 83 Number (%) of Responders a 53 (68.83%) 66 (80.49%) 56 (67.47%) Treatment Comparisons b Difference 95% CI p-value 3 mg/kg BID - Naproxen 1.36% %, 15.80% Naproxen 13.02% -0.22%, 26.25% a A subject was considered a responder by the JRA-30 Definition of Improvement criteria if there was a 30% improvement in 3 JRA-30 Core Set variables and a >30% worsening in at most one JRA-30 Core Set variable. The JRA-30 Core Set includes: 1) Physician s Global Assessment of Disease Activity; 2) Parent s Global Assessment of Overall Well Being (CHAQ subsection); 3) Functional Ability (CHAQ Disability Index); 4) number of joint with active arthritis; 5) number of joints with limited range of motion; 6) laboratory marker of inflammation (C-reactive protein). b Treatment comparisons using Chi-Square test and large sample normal approximation confidence interval. Note: 3 mg/kg BID = 50 mg/5 ml, = 100 mg/5 ml, Naproxen 7.5 mg/kg BID = 125 mg/5 ml. CI = Confidence interval, ITT = Intent-to-treat Secondary Efficacy: Physician s Global Assessment of Disease Activity: Statistically significant results for this endpoint are shown in Table S5. Note that there were no significant results for Weeks 8 and 12. Page 7

8 Table S5 Mean Change Analysis Physician s Global Assessment of Disease Activity (VAS) Double-blind Baseline to Week 12/End of Double-Blind a (ITT Population) 3 mg/kg BID N= 77 N= 82 Naproxen N= 83 Week 2 Mean Baseline (SD) (19.89) (17.35) (16.05) Mean Change from Baseline (SD) (12.75) (14.85) (13.21) LSMean Change from Baseline (SE) b (1.47) (1.43) (1.42) Treatment Comparisons c Difference 95% CI p-value 3 mg/kg BID vs naproxen , Week 4 Mean Baseline (SD) (19.89) (17.35) (16.05) Mean Change from Baseline (SD) (16.31) (16.62) (16.88) LSMean Change from Baseline (SE) b (1.69) (1.64) (1.63) Treatment Comparisons c Difference 95% CI p-value 3 mg/kg BID vs naproxen , a Double-blind baseline is the last observation prior to the first dose of double-blind study medication. This scale ranges from Higher scores indicate poorer well-being. A negative mean change indicates improvement in well-being. b From ANCOVA model with treatment group as a factor and Baseline as covariate. c From a contrast statement from ANCOVA model in footnote b. Note: Only significant comparisons are shown. For Weeks 2 and 4 the celecoxib versus naproxen and the celecoxib 3 mg/kg BID versus celecoxib comparisons were nonsignificant. All comparisons for Weeks 8 and 12 were nonsignificant. 3 mg/kg BID= 50 mg/5ml, celecoxib = 100 mg/5ml, naproxen = 125 mg/5ml CI= Confidence interval, ITT = Intent-to-treat, LS = Least squares, SD = Standard deviation, SE = Standard error Parent s Global Assessment of Overall Well-Being (CHAQ Subsection): The decreases in LS mean change from Baseline to Week 12 were greater for the celecoxib ( mm) and naproxen ( mm) treatment groups than for the celecoxib 3 mg/kg BID ( mm) treatment group. However, no statistically significant between-group differences were observed. Parent s Assessment of Physical Function (CHAQ Disability Index): The decreases in LS mean changes in CHAQ Disability Index score from Baseline to Week 12 were comparable among the 3 treatment groups (-0.28, -0.32, and for celecoxib 3 mg/kg BID, celecoxib, and naproxen, respectively). No statistically significant between-group differences were observed. Number of Joints With Active Arthritis: Statistically significant results for this endpoint are shown in Table S6. Note that there were no significant results for Weeks 2, 4 or 8. Page 8

9 Table S6 Number of Joints With Active Arthritis a Double-blind Baseline to Week 12/End of Double-blind b (ITT) Mean Change Analysis 3 mg/kg BID N= 77 N= 82 Naproxen N= 83 Week 12 Mean Baseline (SD) 8.12 (9.29) 6.68 (8.56) 6.08 (5.99) Mean Change from Baseline (SD) (5.05) (6.02) (4.74) LSMean Change from Baseline (SE) c (0.49) (0.47) (0.47) Treatment Comparisons d Difference 95% CI p-value 3 mg/kg BID vs celecoxib , a A joint was considered active if it was swollen (not due to currently inactive synovitis or to bony enlargement from previously active disease). If no swelling was present, the joint was considered active if it has limited range of motion accompanied by pain or tenderness. Pain and/or tenderness alone were not sufficient for classification of the joint as being active. b Double-blind Baseline is the last observation prior to the first dose of double-blind study medication. c From ANCOVA model with treatment group as a factor and Baseline value as covariate. d From a contrast statement from ANCOVA model in table footnote b. Note: Only statistically significant comparisons are shown. All comparisons for Weeks 2, 4, and 8 were nonsignificant. For Week 12, the celecoxib 3 mg/kg BID versus naproxen and the celecoxib 6 mg/kg BID versus naproxen comparisons were nonsignificant. 3 mg/kg BID= 50 mg/5ml, celecoxib = 100 mg/5ml, naproxen = 125 mg/5ml CI = Confidence interval, ITT = Intent-to-treat, LS = Least squares, SD = Standard deviation, SE = Standard error Number of Joints With Limited Range of Motion: Statistically significant results for this endpoint are shown in Table S7. Note that there were no significant differences between treatment groups for Weeks 2 and 4. Page 9

10 Table S7 Mean Change Analysis Number of Joints With Limited Range of Motion Double-blind Baseline to Week 12/End of Double-blind a (ITT) 3 mg/kg BID N= 77 N= 82 Naproxen N= 83 Week 8 Mean Baseline (SD) 6.60 (8.76) 6.26 (8.25) 4.70 (5.24) Mean Change from Baseline (SD) (4.26) (4.36) (3.11) LSMean Change from Baseline (SE) b (0.38) (0.37) (0.36) Treatment Comparisons c Difference 95% CI p-value 3 mg/kg BID vs celecoxib , Week 12 Mean Baseline (SD) 6.60 (8.76) 6.26 (8.25) 4.70 (5.24) Mean Change from Baseline (SD) (4.89) (4.66) (3.36) LSMean Change from Baseline (SE) b (0.43) (0.42) (0.42) Treatment Comparisons c Difference 95% CI p-value 3 mg/kg BID vs celecoxib , a Double-blind Baseline is the last observation prior to the first dose of the double-blind study medication. b From ANCOVA model with treatment group as a factor and Baseline value as a covariate. c From a contrast statement from ANCOVA model in table footnote b. Note: Only significant comparisons are shown. None of the comparisons for Weeks 2 or 4 were significant and no data is shown for those weeks. For both Weeks 8 and 12, comparisons for the celecoxib 3 mg/kg BID versus naproxen and the celecoxib versus naproxen comparisons were nonsignificant. 3 mg/kg BID= 50 mg/5ml, celecoxib = 100 mg/5ml, naproxen = 125 mg/5ml CI = Confidence interval, ITT = Intent-to-treat, LS = Least squares, SD = Standard deviation, SE = Standard error Laboratory Marker of Inflammation (C-Reactive Protein): There were no statistically significant differences between groups. Pharmacokinetic, Pharmacodynamic, and/or Other Results: plasma concentration data from 187 JRA and adult RA subjects were analyzed using a population PK modeling approach. There were 72 subjects with 266 observations in the celecoxib 3 mg/kg BID treatment group, 79 subjects with 279 observations in the celecoxib treatment group, and 36 subjects with 252 observations in the adult RA celecoxib 200 mg BID cohort. Body weight and gender were identified as predictive covariates of celecoxib clearance. Mean celecoxib Apparent Oral Clearance Adjusted for the Fraction of Drug Absorbed (CL/F, L/h) was 32% lower in children 2 to 5 years relative to adult RA subjects. Mean CL/F (L/h) in children >5 to 11 and >11 to <17 years were 26% lower and 2% higher than in adult RA subjects, respectively. Comparison of low-dose (celecoxib 3 mg/kg BID) and high-dose (celecoxib ) treatments with adult RA subjects indicated that the geometric mean (GM) ratios for pediatric to adult AUC(0-12) were 47.44% (90% CI, ) and 84.29% (90% CI, ), respectively. Comparison of AUCs for each age group with adult AUC indicate that AUC(0-12) of celecoxib was lower in children 2 to 5 years with GM ratios of 27.80% (90% CI, ) and 59.42% (90% CI, ) for the celecoxib 3 and 6 Page 10

11 mg/kg BID dose groups, respectively. At the celecoxib dose, AUC(0-12) in children >5 to 11 years and adolescents >11 to <17 years were comparable (GM ratios of 93.37% and 90.31%, respectively) to that in adult RA subjects. Nevertheless, the percentages of JRA- 30% responders were not lower in 2 to 5 year olds compared with those in older children. Safety Results: During the double-blind phase of the study (Baseline to Week 12), treatmentemergent AEs were reported for a total of 166 subjects: 49 (63.6%) subjects in the celecoxib 3 mg/kg BID treatment group, 57 (69.5%) subjects in the celecoxib treatment group, and 60 (72.3%) subjects in the naproxen treatment group. The most commonly occurring AEs in the celecoxib treatment group were headache not otherwise specified (NOS) (9.8%); pyrexia (8.5%); arthralgia, abdominal pain NOS and cough (each 7.3%); abdominal pain upper, vomiting NOS, and nasopharyngitis (each 6.1%). The most commonly occurring AEs in the naproxen treatment group were headache NOS (15.7%); nausea, vomiting, and pyrexia (each 10.8%); abdominal pain upper (9.6%); diarrhea NOS and cough (8.4%); and abdominal pain NOS (7.2%). Frequent AEs ( 5%) are shown in Table S8. Page 11

12 Table S8 Incidence of Adverse Events Occurring in 5.0% of Subjects in Any Treatment Group a,b in Decreasing Frequency Within a System Organ Class System Organ Class/ Adverse Event Preferred Term 3 mg/kg BID (N = 77) (N = 82) Naproxen (N = 83) Any Event, N (%) 49 (63.6) 57 (69.5) 60 (72.3) Eye Disorders 4 (5.2) 4 (4.9) 4 (4.8) Gastrointestinal Disorders 20 (26.0) 20 (24.4) 30 (36.1) Abdominal Pain NOS 3 (3.9) 6 (7.3) 6 (7.2) Abdominal Pain Upper 6 (7.8) 5 (6.1) 8 (9.6) Vomiting NOS 2 (2.6) 5 (6.1) 9 (10.8) Diarrhea NOS 4 (5.2) 3 (3.7) 7 (8.4) Nausea 5 (6.5) 3 (3.7) 9 (10.8) General Disorders and Administration Site Conditions 10 (13.0) 9 (11.0) 15 (18.1) Pyrexia 6 (7.8) 7 (8.5) 9 (10.8) Infections and Infestations 19 (24.7) 16 (19.5) 22 (26.5) Nasopharyngitis 4 (5.2) 5 (6.1) 4 (4.8) Injury and Poisoning 3 (3.9) 5 (6.1) 4 (4.8) Investigations 2 (2.6) 9 (11.0) 6 (7.2) Musculoskeletal, Connective Tissue, and Bone Disorders 6 (7.8)* 8 (9.8) 14 (16.9) Arthralgia 2 (2.6) 6 (7.3) 3 (3.6) Nervous System Disorders 13 (16.9) 9 (11.0) 17 (20.5) Headache NOS 10 (13.0) 8 (9.8) 13 (15.7) Dizziness (excluding vertigo) 1 (1.3) 1 (1.2) 6 (7.2) Respiratory, Thoracic, and Mediastinal Disorders 6 (7.8) 12 (14.6) 12 (14.5) Cough 5 (6.5) 6 (7.3) 7 (8.4) Skin & Subcutaneous Tissue Disorders 8 (10.4) 6 (7.3)* 15 (18.1) a Includes only TESS AEs that were reported up to 28 days after the last dose of study medication. b If a subject had more than 1 AE within a system organ class, that subject is counted once in the overall incidence for that system organ class. *p-value 0.10 in system organ class from pairwise comparison with naproxen using Fisher s Exact test. 3 mg/kg BID = 50 mg/5 ml; = 100 mg/5 ml; Naproxen 7.5 mg/kg BID = 125 mg/5 ml. NOS = Not otherwise specified Gastrointestinal (GI) disorders were the AEs most frequently reported as severe in any treatment group. Thirty-one (12.8%) subjects experienced AEs during the double-blind phase of the study that Investigators considered related to study medication: 11 subjects (14.3%) in the celecoxib 3 mg/kg BID treatment group, 10 (12.2%) subjects in the celecoxib treatment group, and 10 (12.0%) naproxen subjects in the treatment group. A small number of subjects withdrew from the study due to AEs. A summary is shown in Table S9. Page 12

13 Table S9 Incidence of Adverse Events Causing Permanent Discontinuation from the Double-Blind Phase of the Study a, b System Organ Class/ Adverse Event Preferred Term 3 mg/kg BID N= 77 N= 82 Naproxen 7.5 mg/kg BID N= 83 Any Event, n (%) 3 (3.9) 7 (8.5) 3 (3.6) Gastrointestinal Disorders 2 (2.6) 0 (0.0) 2 (2.4) Abdominal pain NOS 1 (1.3) 0 (0.0) 0 (0.0) Adbominal pain upper 0 (0.0) 0 (0.0) 2 (2.4) Dysphagia 1 (1.3) 0 (0.0) 0 (0.0) Esophageal pain 1 (1.3) 0 (0.0.) 0 (0.0) Vomiting NOS 0 (0.0) 0 (0.0) 1 (1.2) Immune system disorders 0 (0.0) 1 (1.2) 0 (0.0) Hypersensitivity NOS 0 (0.0) 1 (1.2) 0 (0.0) Infections and Infestations 1 (1.3) 0 (0.0) 0 (0.0) Hepatitis cytomegalovirus 1 (1.3) 0 (0.0) 0 (0.0) Investigations 0 (0.0) 3 (3.7) 0 (0.0) Hematuria present 0 (0.0) 1 (1.2) 0 (0.0) Liver function tests NOS 0 (0.0) 1 (1.2) 0 (0.0) abnormal Transaminase NOS 0 (0.0) 1 (1.2) 0 (0.0) increased Musculoskeletal, connective 0 (0.0) 1 (1.2) 1 (1.2) tissue & bone disorders Juvenile rheumatoid arthritis 0 (0.0) 1 (1.2) 1 (1.2) Respiratory, thoracic & 0 (0.0) 1 (1.2) 0 (0.0) mediastinal disorders Asthma 0 (0.0) 1 (1.2) 0 (0.0) Skin & subcutaneous tissue 0 (0.0) 1 (1.2) 0 (0.0) disorders Rash generalized 0 (0.0) 1 (1.2) 0 (0.0) a Includes only TESS AEs b A subject is counted once for each AE reported as causing withdrawal. 3 mg/kg BID = 50 mg/5 ml; = 100 mg/5 ml; Naproxen 7.5 mg/kg BID = 125 mg/5 ml. NOS = Not Otherwise Specified. Three subjects (3.9%) in the celecoxib 3 mg/kg BID treatment group and 2 subjects (2.4%) in the celecoxib treatment group experienced serious AEs during the double-blind phase of the study. In the celecoxib 3 mg/kg BID treatment group, abdominal pain NOS, acute cytomegalovirus (CMV) hepatitis, and viral infection NOS were reported as serious. In the celecoxib treatment group, exacerbations of JRA and asthma were reported as serious. Only the abdominal pain NOS and exacerbation of asthma events were considered be related to treatment. Four subjects (2.0%) in the open-label phase experienced serious AEs, none of which were considered to be related to the study drug. Of the 43 adult RA subjects enrolled in the open-label phase of the study, 5 (11.6%) experienced AEs (Table S10). Two subjects who experienced AEs withdrew from the study. One subject Page 13

14 withdrew due to mild diarrhea and dizziness and another withdrew due to moderate urticaria. Both subjects recovered from these events. No adult subjects experienced serious AEs. Table S10 Adverse Events in Adult Cohort (ITT Population)* System Organ Class Adverse Event (MeDRA) 200 mg BID N (%) Treated patients 43 (100%) Any event 5 (11.6) Gastrointestinal disorder 4 (9.3) Diarrhea NOS 2 (4.7) Duodenal polyp 1 (2.3) Dyspepsia 1 (2.3) Gastritis NOS 1 (2.3) Infections and infestations 1 (2.3) Ear infection NOS 1 (2.3) Neoplasms benign & malignant (including cysts and 1 (2.3) polyps) Barrett s esophagus 1 (2.3) Nervous system disorders 1 (2.3) Dizziness (excluding vertigo) 1(2.3) Skin & subcutaneous tissue disorders 1 (2.3) Uriticaria NOS 1 (2.3) *Baseline is the last observation prior to the first dose of study medication. If a patient had more than 1 AE within a system organ class that patient was counted once in the overall incidence for that system organ class. There were no deaths in this study. Mean changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were not clinically meaningful. Overall mean changes in clinical laboratory values were not considered clinically meaningful. Individual subjects within each treatment group had clinical laboratory values that were clinically relevant. CONCLUSION(S): at doses of 3 and was as effective as naproxen in treating the signs and symptoms of JRA, as judged by a non-inferior response in the JRA- 30 criterion. Treatment differences favored celecoxib over celecoxib 3 mg/kg BID at all time points and naproxen at Weeks 4, 8, and 12. at doses of 3 and was as effective as naproxen in subjects with pauciarticular or polyarticular course JRA as judged by non-inferior response in the JRA-30 criterion at Week 12. There were no apparent differences in the rates of systemic flare in celecoxib-treated versus naproxen-treated subjects. The efficacy response to celecoxib was durable as evidenced by similar efficacy results after 6 months of treatment as after 12 weeks. at doses of 3 and had no observable deleterious effect on growth Page 14

15 or development. at doses of 3 and was safe and well tolerated in children aged 2 to 16 years with JRA, relative to naproxen. AUC(0-12) at a dose of was lower in children 2 to 5 years and similar in children >5 to <17 years when compared to adult subjects with RA receiving 200 mg BID. Nonetheless, the systemic exposure of celecoxib in JRA subjects was well within the range of exposures observed with labeled doses (100 to 200 mg BID) in adult subjects with RA. Page 15